Brophy D F, Israel D S, Pastor A, Gillotin C, Chittick G E, Symonds W T, Lou Y, Sadler B M, Polk R E
Schools of Pharmacy, Virginia Commonwealth University/Medical College of Virginia Campus, Richmond, VA 23298-0533, USA.
Antimicrob Agents Chemother. 2000 Apr;44(4):978-84. doi: 10.1128/AAC.44.4.978-984.2000.
The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin. To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers. This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study. Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUC(ss), C(max,ss), and C(min,ss) by 18, 15, and 39%, respectively. Amprenavir had no significant effect on the AUC(ss) of clarithromycin, but the median T(max,ss)for clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUC(ss) for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin. A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug.
细胞色素P450酶CYP3A4可对安普那韦和克拉霉素进行广泛代谢。为确定这两种药物合用时是否存在相互作用，对健康成年男性志愿者的安普那韦和克拉霉素的药代动力学进行了研究。这是一项I期、开放标签、随机、平衡、多剂量、三周期交叉研究。14名受试者接受了以下三种治疗方案：安普那韦，每日两次，每次1200mg，共4天（七剂）；克拉霉素，每日两次，每次500mg，共4天（七剂）；以及上述两种方案联合使用4天（每种药物七剂）。12名受试者完成了所有治疗及随访期。在基线、三种治疗方案最后一剂后2小时以及首次随访时进行红霉素呼气试验（ERMBT）。克拉霉素与安普那韦合用时，安普那韦的平均AUC(ss)、C(max,ss)和C(min,ss)分别显著增加了18%、15%和39%。安普那韦对克拉霉素的AUC(ss)无显著影响，但克拉霉素的中位T(max,ss)增加了2.0小时，肾脏清除率增加了34%，与安普那韦合用时14-(R)-羟基克拉霉素的AUC(ss)降低了35%。安普那韦和克拉霉素分别使ERMBT结果降低了85%和67%，两种药物合用时降低了87%。基线ERMBT值与安普那韦或克拉霉素的清除率无关。安普那韦和克拉霉素合用时会发生药代动力学相互作用，但这种影响在临床上可能并不重要，两种药物合用时均无需调整剂量。
